PROJECT SUMMARY Although the inner workings of the cochlea are responsible for the most fundamental aspects of hearing, including hearing sensitivity and frequency tuning, our direct knowledge of human cochlear mechanics is limited. This lack of information has forced researchers to rely on animal experiments to make inferences about cochlear behavior in humans, under the assumption that the motions of the cochlear partition (CP), including the basilar membrane (BM) and the organ of Corti (OoC), are similar between humans and laboratory animals. However, we have recently found surprising differences in human CP anatomy and motion as compared to laboratory animals. The BM in animals is attached to a narrow fixed bony structure, the osseous spiral lamina (OSL), and accounts for almost all of the CP motion. In contrast, the OSL in humans is much wider, is mobile, and connects to the BM via a newly identified soft-tissue structure that we have named the CP ?bridge?. The bridge, which is non-existent in laboratory animals, is as wide as and vibrates as much as the BM. Combined with the fact that the OSL itself is mobile, the BM therefore only accounts for a fraction of total CP motion in humans. These newly discovered aspects of human CP anatomy and motion challenge the long-held assumption that cochlear mechanics can be regarded as similar across mammals. Because CP structures such as the OSL, bridge, and location where the tectorial membrane (TM) attaches to the limbus are all mobile in humans but not in laboratory animals, we hypothesize that the motions of the OoC structures, including the reticular lamina and TM, are different in humans, thereby altering the input driving the transduction process at the hair bundles of the inner and outer hair cells. To test this, Optical Coherence Tomography (OCT) will allow us to determine the anatomy and relative motion of various CP structures in situ in very fresh human cadaveric specimens. We will also investigate and elucidate the relationships between mechanics and anatomy in the human CP using a variety of techniques to characterize the morphometry, structural architecture, and material composition of the CP. We will further test our hypothesis by developing finite-element models of the human cochlea that incorporate the measured anatomy and CP mechanics. As our measurements are from postmortem ears, they cannot reveal the effects of active processes. However, our models can approximate active behavior based on live-animal results, which are predicted to be functionally similar to human given the similar anatomies of these structures. The resulting models will be tested and validated against known human tuning capabilities from psychoacoustic data, opening the door to future applications in which human cochlear pathologies, manipulations, and treatments can be simulated with unprecedented fidelity. This research will greatly advance our understanding of how the structures of the human CP work together to define the inputs to the transducers formed by the hair cells. It will also enable us to better understand the applicability and limitations of animal experiments in the study of human hearing, and to better utilize animal models for scientific inquiry. Moreover, the proposed computational models will be valuable both for scientific investigation of hearing phenomena and for future improvements in the understanding, diagnosis and treatment of hearing disease.